The present invention relates to dosage forms containing an extruded polymer tube. More specifically, the invention relates to polymer tube forms prepared by extrusion for the manufacture of osmotic dosage forms for administration of a therapeutic agent.
One focus of efforts to improve drug therapy has been directed to providing drug dosage forms that provide controlled release of drug to the environment of use. Examples of such delivery systems include delayed-release and sustained-release systems. A particular approach to providing sustained release dosage forms that has found commercial success involves osmotic delivery systems, as described, for example, in U.S. Pat. Nos. 3,845,770 and 3,916,899. Osmotic dosage forms, in general, utilize osmotic pressure to generate a driving force for imbibing fluid into an internal compartment formed, at least in part, by a semipermeable wall that permits free diffusion of fluid but not drug or osmotic agent(s), if present. Following administration of the dosage form to a suitable fluid environment, such as the gastrointestinal tract or other body cavity or body tissue, fluid imbibition results in a deliverable drug-containing formulation being released from within the compartment through a suitable exit means formed through the semipermeable membrane. The rate of drug release is determined by the osmotic driving force.
Osmotic systems may be manufactured by forming the active agent and other ingredients for the internal compartment, such as an osmagent and osmopolymer, into a solid or semisolid by ballmilling, calendaring, stirring or rodmilling and then pressing into a preselected shape. The semipermeable wall material is dissolved in an appropriate solvent such as acetone or methylene chloride and is then applied to the pressed shape by molding, air spraying, dipping or brushing a solvent-based solution of the wall material onto the shape (U.S. Pat. Nos. 4,892,778, 4,285,987). Other methods for applying the semipermeable wall include an air suspension procedure, where the pressed shape is suspended and tumbled in a current of air and wall forming material (U.S. Pat. No. 2,799,241), and a pan coating technique. After application of the semipermeable wall to the pressed shape, a drying step is required and, then, suitable exit means for the active agent must be formed through the semipermeable membrane. Depending on the properties of the active agent and other ingredients within the internal compartment and the desired release rate for the dosage form, one or more orifices for active agent delivery are formed through the semipermeable membrane by mechanical drilling, laser drilling, or the like. The orifice may range in size from a single large orifice containing substantially an entire surface of the dosage form to one or more small orifices selectively located on the surface of the semipermeable membrane.
Dosage forms prepared by solvent-coating the semipermeable wall onto the pressed shape have been commercially successful, providing controlled and continuous release of various active agents to a variety of environments. There is, however, a need to improve the manufacture of the dosage forms. As mentioned above, the semipermeable wall is typically manufactured using an organic solvent such as acetone or methylene chloride. Manufacture of the wall via an organic solvent deposition process yields excellent membranes however there are disadvantages associated with the use of solvents. The solvents can be expensive, they are explosive, traces can be toxic and their use has a negative environmental impact. Further, after deposition of the semipermeable wall, the solvent must be removed by drying, requiring a further time-consuming processing step. After solvent removal, suitable exit means for the active agent must be provided by a drilling step requiring additional equipment and labor.
One approach to the manufacture of the above-described devices utilizing an injection molding process for manufacturing the semipermeable wall is described in U.S. Pat. No. 5,830,502. This process provides a dosage form prepared without the use of organic solvents. However, the injection molding process involves the use of specifically designed molds that can be expensive, as are the molding machinery and auxiliary equipment.
There is a remaining need to provide another approach for the manufacture of dosage forms having such a semipermeable wall. Ideally, this approach would reduce or eliminate some of the processing steps required by methods described above, such as solvent deposition of the semipermeable wall, solvent removal and drilling of suitable active agent exit means.
In one aspect, the present invention provides osmotic dosage forms and methods for manufacturing osmotic dosage forms having membranes that are essentially free of organic solvents. In this manner, problems associated with the storage, handling and use of such solvents are eliminated. In addition, the number of processing steps is reduced and processing time is decreased because the need for solvent drying is eliminated.
In another aspect, the present invention provides methods for manufacturing osmotic dosage forms having membranes that do not require a drilling step to form exit means for the therapeutic agent.
The invention is directed to osmotic dosage forms for delivery of a therapeutic agent comprising an internal compartment formed, at least in part, by a semipermeable wall that permits free diffusion of fluid but not therapeutic agent(s) or osmotic agent(s) wherein the semipermeable membrane comprises an extruded polymer tube. Disposed within the internal compartment is (i) a therapeutic agent and (ii) an expandable composition capable of absorbing biological fluid from an environment of use to thereby expand within the internal compartment and facilitate delivery of the therapeutic agent out of the internal compartment. The polymer tube circumscribes the internal compartment and is open at each end. Depending on the properties of the active agent and other ingredients within the internal compartment and the desired release rate for the dosage form, release of therapeutic agent may occur through either an open tube end (or ends) or through a suitably sized orifice, smaller than the open tube end, configured at the tube end(s). Such an orifice is formed, for example, by crimping or heat-sealing or the like, of the tube end to close the end except for a suitably sized orifice.
In certain embodiments, release of therapeutic agent occurs at both tube ends while, in other embodiments, release occurs at only one tube end. In these other embodiments, the tube end opposite to the tube end where therapeutic agent is released is preferably configured to be partially or completely closed to ensure that the adjacent component of the internal compartment remains in place within the internal compartment. Accordingly, the size of the polymer tube with respect to the size of the internal compartment is adapted to accommodate the need, when present, to close either or both of the tube ends.
In certain embodiments, the dosage form includes a first layer containing therapeutic agent adjacent one end of the polymer tube and a second layer containing the expandable composition adjacent the other tube end. If desired, additional layers containing therapeutic agent(s) may also be included in the internal compartment between the therapeutic agent layer adjacent one tube end and the expandable composition adjacent the opposite tube end. In these embodiments, therapeutic agent will be released from the tube end adjacent to the therapeutic agent layer(s) following administration of the dosage form. Accordingly, depending on the properties of the active agent and other ingredients within the internal compartment and the desired release rate for the dosage form, this tube end may be left open or may be closed to an extent that provides a suitably sized orifice for the delivery of the therapeutic agent(s) therethrough. The opposite tube end, adjacent to the expandable composition, is closed either completely or substantially completely such that the expandable composition is retained within the internal compartment and to ensure that the pushing force generated by the expansion of the composition is substantially directed towards the therapeutic agent layer(s).
In other embodiments, the dosage form includes a first layer containing therapeutic agent adjacent one end of the polymer tube and a second layer containing therapeutic agent adjacent the other tube end with the expandable composition disposed between the first and second layers of therapeutic agent. The first and second layers containing therapeutic agent may comprise the same or different therapeutic agents. If desired, additional layers containing therapeutic agent(s) may also be included in the internal compartment on either side of the expandable composition. In these embodiments, therapeutic agent(s) will be released from both ends of the polymer tube following administration of the dosage form. Accordingly, depending on the properties of the active agent and other ingredients within the internal compartment and the desired release rate for the dosage form, either or both of the tube ends may be left open or may be closed to an extent that provides a suitably sized orifice for the delivery of the therapeutic agent(s) therethrough.
In still other embodiments, the dosage form further includes a non-expandable, inert, hydrophobic layer within the internal compartment that is positioned adjacent to one of the tube ends and also adjacent to the expandable composition. For example, the expandable composition can take the form of a discrete layer sandwiched between the nonexpandable layer on one side and a therapeutic agent layer on the other side such that the therapeutic agent layer is adjacent the other tube end. If desired, additional layers containing therapeutic agent(s) may also be included in the internal compartment between the therapeutic agent layer adjacent the tube end and the expandable layer. In these embodiments, therapeutic agent(s) will be released from just one end of the polymer tube following administration of the dosage form. Accordingly, depending on the properties of the active agent and other ingredients within the internal compartment and the desired release rate for the dosage form, the tube end adjacent to a therapeutic agent layer may be left open or may be closed to an extent that provides a suitably sized orifice for the delivery of the therapeutic agent(s) therethrough. The tube end adjacent to the nonexpandable layer is preferably closed to an extent sufficient to ensure that the nonexpandable layer remains in place within the internal compartment.
In still another embodiment, the extruded polymer tube is composed of a polycaprolactone copolymer selected from the group consisting of polycaprolactone dilactide copolymer, polycaprolactone diglycolide, polycaprolactone valerolactone and polycaprolactone decaloactone. In one preferred embodiment, the extruded polymer tube is composed of a polycaprolactone and polyalkyleneoxide polymer blend.
The present invention is further directed to methods for manufacturing the dosage forms herein described. The methods include extruding a polymer into a tube form for circumscribing an internal compartment having first and second open ends, the polymer tube providing a semipermeable wall that permits free diffusion of fluid but not therapeutic agent or osmotic agent(s) and introducing into the internal compartment (i) a therapeutic agent and (ii) an expandable composition capable of absorbing biological fluid, following administration of the dosage form, to thereby expand and force the therapeutic agent to be released from the dosage form through either an open tube end or through an orifice formed in a tube end.
Optionally, a further step of configuring either or both of the tube ends, may be required. Depending on the properties of the active agent and other ingredients within the internal compartment and the desired release rate for the dosage form i.e., either or both of the open tube ends may be configured to be partially or fully closed, as by crimping or heat-sealing or the like. The extent of closure is determined by the specific purpose which may be either to ensure that a component of the internal compartment adjacent to the tube end remains in place within the internal compartment or to provide a suitably sized orifice, smaller than the open tube end, for delivery therethrough of therapeutic agent from within the internal compartment.
In one embodiment of this aspect, the step of introducing includes (i) placing component layers as described above, i.e., therapeutic agent layer(s), an expandable layer and a non-expandable layer, if included, in a selected order within the extruded tube to ensure that the appropriate layers are adjacent the tube ends. If desired, some or all of the discrete component layers may initially be compressed into a multi-layer tablet using a tablet press device and the compressed multi-layer tablet is then introduced into the internal compartment of the extruded tube. The remaining component layers, if any, are then placed into the tube and the step of configuring the tube ends, if needed, is performed.
These and other objects and features of the invention will be more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings.